The principle goal of this grant continues to be elucidation of the early developmental events in the embryonic cerebral cortex that precede formation of synaptic connections. Our basic strategy remains to conduct studies of cellular and molecular mechanisms of neuronal proliferation, commitment and migration that determine the size of the neocortex as well as the laminar and areal positions of neurons in rodents and primates, including human. We hypothesize that even a small mal-position of neurons, which eventually affects development of their synaptic connections, and thus indirectly, the quality of their function, may underlay a variety of cognitive disorders with unknown pathology, such as autism, childhood epilepsy, developmental dyslexia, schizophrenia and mental retardation. In Specific Aim #1 we use the most advanced methods, including the triple KO technology, electroporation and multi-photon microscopy both in vivo and in vitro, to continue our analysis of the molecular mechanisms of neuronal migration including the role of Notch/RBP-J and EphA/ephrin-A signaling in regulation of phenotype specification, radial allocation and final positioning in cortical columns. In Specific Aim #2 we will continue and expand our study of abnormal neuronal production and migration due to the effect of ultrasound waves (USW) on neuronal proliferation and migration to the cerebral cortex of non-human primates. The already published data of over-production and malposition of cortical neurons in postnatal mice exposed to therapeutic drugs and USW as embryos, and our strong preliminary data, so far obtained in macaque monkeys, requires examination of additional time points and numbers of animals to make a definitive conclusion. These Specific Aims are built upon the considerable progress that we have made in the last cycle of this long-standing and high impact research grant, and are essential for understanding the pathogenesis of a host of genetic and acquired congenital malformations affecting human cognitive capacity. PUBLIC HEALTH RELEVANCE: The identity, synaptic connections and physiology of neurons that underlie the highest cognitive functions in the adult cerebral cortex are to a great extent defined by their laminar, columnar and areal positions that are achieved during early embryonic development by active and precise orchestration of neuronal production and migration from multiple sites of origin. The disruption or even slight slowing of migration by either genetic or environmental factors may results in failure of the proper number of neurons to reach their "addresses" and cause either large malformations that are easily detectable, or a subtle misplacement of individual neurons that could be entirely missed by routine examination in both alive or autopsied human brains. We hypothesize that even small elimination or slight dislocation of neurons may be involved in a variety of idiopathic neurological disorders that range from childhood epilepsy and mental retardation to schizophrenia, autism and developmental dyslexia. Thus, we propose to continue our investigation of cellular and molecular mechanisms of normal and abnormal cortical neurogenesis to obtain new insight into the causes of these disorders that may lead to their prevention or therapy.